“Final IMPRESS overall survival [OS] results are sufficient to warn doctors against the continuation of treatment with first-generation EGFR TKIs beyond radiological disease progression”, said presenting author Tony Mok, from the Chinese University of Hong Kong, at the ESMO 2016 congress in Copenhagen, Denmark.

Previous reports from the trial showed comparable rates of progression-free survival (PFS), overall response and disease control for patients who progressed after an initial response to gefitinib therapy and who continued with the EGFR tyrosine kinase inhibitor (TKI) during chemotherapy with cisplatin plus pemetrexed (n=133) and those who were given placebo with the chemotherapy (n=132).

However, the final OS results from the phase III trial demonstrated that continuing gefitinib during chemotherapy was associated with a significantly poorer outcome, with a median OS of 13.4 months versus 19.5 months for placebo plus chemotherapy, giving a hazard ratio (HR) of 1.44 in favour of chemotherapy alone.

Further analysis failed to identify any significant signal to explain why continuing gefitinib should decrease OS, showing universally poorer OS across all subgroups, and additional covariate OS analysis adjusting for brain metastases and T790M mutation status confirmed the “genuine detrimental effect” with an HR of 1.31.

There was also no safety signal to account for differences in OS between the treatment groups, although analysis of post-discontinuation therapy showed that patients who continued with gefitinib were less likely to receive further treatment than those who were given placebo (60.6 vs 71.2%) and, in particular, less likely to receive further EGFR TKI therapy (22.7 vs 36.4%).

Plasma circulating tumour DNA biomarker analysis was performed on baseline samples from 98% of patients and showed that 40.2% of patients did not have the T790Mmutation.

T790Mmutation-positive patients who continued with gefitinib had significantly shorter OS than their placebo-treated counterparts, at 10.8 versus 14.1 months and an HR of 1.49. By contrast, OS in the mutation-negative patients was comparable in the two arms of the trial, at 21.4 versus 22.5 months and a nonsignificant HR of 1.15.

However, Tony Mok emphasized that T790M status is not always accurate when measured by plasma circulating tumour DNA, so that results can be described as informative (ie, when test detects exon 19 deletion or L858R mutation but not T790M, implying true T790M mutation-negative) or non-informative (when test is unable to detect any mutations, indicating inadequate circulating tumour cells).

Exploratory analysis suggested that informative status was associated with tumour burden, so that patients with informative results had a higher incidence of distant metastases (96 vs 79%) and malignant pleural effusion (32 vs 19%) than those with non-informative plasma samples.

And when looking at OS in patients with a T790M mutation-negative informative status – those with a “true negative” status – the median was 18.4 months with gefitinib versus 19.5 months for placebo, giving a nonsignificant HR of 0.93.

Tony Mok therefore concluded that the results indicate that T790M mutation-positive patients should be considered for third-generation EGFR TKI therapy but suggested that it is “still unclear” what the best strategy may be for patients without this resistant mutation.

Discussant Pasi Jänne, from Dana-Farber Cancer Institute in Boston, Massachusetts, USA, reviewed the current status of EGFR TKI therapy in NSCLC, noting that there are three first-line options in 2016 – erlotinib, gefitinib and afatinib.

He agreed that EGFR TKI therapy should be discontinued when switching to chemotherapy and noted the better OS in patients without the T790M mutation than those positive for the mutation is contrary to earlier reports.

He emphasized that the third-generation EGFR TKI osimertinib offers an alternative to chemotherapy after progression on first-line EGFR TKI for patients with the T790Mmutation, with positive PFS results from the AURA3 phase III study comparing the agent with chemotherapy expected later this year.

But in the future osimertinib may indeed become the first-line option for patients, with further questions on how best to treat patients after progression with potential combinations of EGFR TKIs, chemotherapy and immunotherapy.